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Available online at www.sciencedirect.com
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Inflammatory bowel disease and risk of coronary heart disease Christine Rungoen, Nynne Nyboe Andersen, and Tine Jess Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen, Denmark
abstra ct Emerging data have shown consistent evidence of an association between inflammation and development of atherosclerosis. Systemic autoimmune diseases are characterized by chronic inflammation and immune dysregulation, and diseases such as rheumatoid arthritis and lupus erythematosus are now commonly accepted to associate with development of cardiovascular disease, including coronary artery disease. However, the risk of cardiovascular disease in inflammatory bowel disease (IBD), a chronic inflammatory disease of the gut, is still unclear and the magnitude of a potentially increased risk is continuously debated. The aim of this review is to give an update on the existing literature on the association between inflammatory bowel disease and risk of cardiovascular disease, in particular coronary artery disease, and further to discuss traditional and non-traditional risk factors in patients with inflammatory bowel disease. & 2015 Elsevier Inc. All rights reserved.
Coronary heart disease Coronary heart disease (CHD) and myocardial infarction (MI) are major causes of morbidity and mortality worldwide [1]. In the past, cardiovascular disease prevention has focused on the role of lifestyle risk factors, such as body weight, smoking, cholesterol levels, fat consumption, exercise infrequency, and blood pressure, and the objective has been to reduce the levels of these factors [2]. However, increasing evidence suggests that inflammation plays an essential role in atherogenesis [3], as it acts as a key regulatory process linking multiple risk factors for atherosclerosis [4]. It is, therefore, natural to investigate the occurrence of atherosclerosis among patients with systemic inflammatory diseases. Cardiovascular manifestations of rheumatologic diseases have gradually become recognized, particularly coronary heart disease [5], and it is therefore recommended to monitor patients with rheumatologic diseases carefully to assure early recognition, management, and treatment of cardiovascular disease to improve the long-term outcome in these patients [5]. In patients with inflammatory bowel disease (IBD), evidence The authors have indicated that there are no conflicts of interest. n Corresponding author. Tel.: þ45 207 624 77. E-mail address: [email protected] (C. Rungoe). http://dx.doi.org/10.1016/j.tcm.2015.03.010 1050-1738/& 2015 Elsevier Inc. All rights reserved.
is limited and no management guidelines have been recommended for these patients.
Inflammatory bowel disease Crohn's disease and ulcerative colitis, referred to as inflammatory bowel disease (IBD), are chronic intestinal diseases of multifactorial etiology, ——a result of an interaction between a predisposing genetic background and various environmental factors [6,7]. Ulcerative colitis and Crohn's disease are characterized by a chronic relapsing or continuous disease course with intestinal inflammation, causing gastrointestinal symptoms such as diarrhea, passage of blood, pus, or mucus, abdominal pain, fever, and weight loss. In patients with ulcerative colitis, the inflammation is limited to the mucosal layer of the colon; it almost consistently involves the rectum and extends in a proximal and continuous manner to involve other parts of the colon. Crohn's disease is characterized by transmural inflammation, which can lead to fibrosis and obstructive clinical presentations, and it can occur as skip
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lesions throughout the gastrointestinal tract [8–10]. The incidence of IBD is increasing in North America [11,12], Europe [13], as well as in Asia [14]. Treatment strategies for inflammatory bowel disease primarily focus on reducing the intestinal inflammatory burden, either by surgical treatment or/and by medical treatment. Since the middle of the 20th century, the medical treatment of both Crohn's disease and ulcerative colitis primarily consisted of 5-aminosalicylic acid preparations (5-ASA) and corticosteroids in case of flares. However, in the past 30 years, major advances in medical treatment of IBD have been made, with the introduction of thiopurines and latest tumor necrosis factor alpha (TNFalpha) blockers (late 1990s). Extra-intestinal manifestations in patients with IBD are common, and include, among others, manifestations in the ocular, dermatologic, musculoskeletal, and hepatopancreatobiliary system [15]. The fact that approximately one-third of patients with IBD present with at least one extra-intestinal manifestation has led to the suggestion that IBD is a systemic disorder with predominant manifestations in the bowel. Systemic or local, the inflammatory burden in IBD varies between patients and may relate to disease duration, extent of intestinal involvement, and disease activity. The great heterogeneity in inflammatory burden within the IBD population makes it a challenge to evaluate the overall risk and risk factors for coronary heart disease in patients with IBD. We aimed to review existing literature on the occurrence of cardiovascular disease, with focus on coronary artery disease, among patients with inflammatory bowel disease and to address the controversies that surround it.
Methodology/review criteria Preparing this review, a systematic literature search was performed using PubMed, MEDLINE, and EMBASE databases from inception until January 2015, as well as review of article bibliographies, for all relevant English language articles on the risk of ischemic heart disease in patients with IBD. Search terms used were “ischemic heart disease,” “coronary heart disease,” “myocardial infarction,” “atherosclerosis,” and “thromboembolism/arterial” in combination with key words “inflammatory bowel disease,” “ulcerative colitis,” or “Crohn's disease.”
Inflammatory bowel disease and risk of coronary heart disease The association between venous thromboembolic events and IBD is well established [16], and precautions for hospitalized patients are taken. However, there are no such recommendations for arterial thromboembolic events and the topic is still debatable. In the year 2000, a large registry-based IBD study [17] from Canada was among the first to describe an increased risk of ischemic heart disease (IHD) in a populationbased setting. IBD patients (n ¼ 8060) were found to have a 26% increased risk of ischemic heart disease (IRR ¼ 126; 95% CI: 1.11–1.44) compared to non-IBD patients (n ¼ 80,489). Whereas CD and UC patients had similar risk of IHD, women
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carried a higher risk than men did. In accordance, another population-based study from the US, using data from a discharge database [18], observed that only an increased risk of myocardial infarction in women with IBD aged more than 40 years (HR ¼ 1.6; P ¼ 0.003), after adjustment for potential confounders, including hypertension, diabetes, dyslipidemia, and use of contraceptives. A more substantial risk was described from a smaller single-center study also from the US, which found a 4-fold increased risk of coronary heart events among IBD patients [19] (HR ¼ 4.08; 95% CI: 2.49–6.70) compared to non-IBD patients who were hospitalized for other reasons at the same hospital. Although the authors were able to control for a variety of potential confounders and found IBD patients to have a lower burden of traditional risk factors, their population might not be generalizable, being from a single-center hospital and comprising mostly Hispanic and low-income individuals. A cross-sectional study [20] using a nationwide inpatient sample of IBD patients and hospitalized patients as controls observed an inverse relation between IBD and IHD (OR ¼ 0.60; 95% CI: 0.56–0.65). However, these results may be interpreted with caution, as results might be influenced by selection bias; assessment of a select subset of more severely ill patients in a tertiary center or due to methodological issue; comparison with a selected control population. A study from the UK General Practice Research Database [21] on 15,498 patients with ulcerative colitis and 9829 patients with Crohn's disease, found an increased risk of acute myocardial infarction among IBD patients in analysis without adjustment. However, adjustment for potential confounders including age, sex, previously hypertension, diabetes, hypercholesterolemia, smoking status, body mass index, and aspirin use attenuated the association. However, this might be due to selective assessment of the less severely ill part of the IBD population. A nationwide registry-based Danish study [22] of 4.6 million individuals including 28,833 patients with IBD, observed a modestly increased risk of ischemic heart disease in patients with IBD. The risk of ischemic heart disease (IHD) was 2-fold increased during the first year after IBD diagnosis and approximately 20% increased during 1–13 years after diagnosis when taking age, gender, calendar year, socioeconomic status, use of glucose-lowering medications, cardiovascular drugs, and treatment for hypercholesterolemia into account. Risk estimates were similar in patients with Crohn's disease and ulcerative colitis, whereas women had increased risk compared to that of men. In line with this, a subsequent Danish registry-based study [23] on a similar population, examined risk of myocardial infarction in IBD patients according to proxies for disease activity (dividing time after first IBD diagnosis into periods of flare, persistent activity or remission depended on need of corticosteroids, anti-TNF-alpha treatment, or hospitalization). The authors found that IBD patients had an increased risk of MI during flares (IRR ¼ 1.49; 95% CI: 1.16–1.93), and persistent activity (IRR ¼ 2.05; 95% CI: 158–265), (flares defined as need for medical treatment or hospitalization within 120 days after a flare), but no increased risk during remission (IRR ¼ 1.01; 95% CI: 0.89–1.15) was observed. However, both the risk of ascertainment bias and acute illness (including hypovolemia and anemia), which per se is associated with
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increased short-term risk of cardiovascular events, may contribute to this association. However, in line with this, a Swedish study [24] examined the risk of coronary heart disease among patients hospitalized for immune-mediated diseases including ulcerative colitis and Crohn's disease also observed an increased risk of coronary heart disease among hospitalized patients with UC (SIR ¼ 1.21; 95% CI: 1.17–1.26), and a very modestly increased risk in patients with CD (SIR ¼ 1.06; 95% CI: 1.01–1.12), after adjustment for age, period, socioeconomic factor and hospitalization chronic lower respiratory disease, obesity, alcoholism, hypertension, diabetes, arterial flutter or heart failure and renal disease). A systematic review and meta-analysis [25] on risk of cardiovascular disease in IBD patients, including nine studies (six case–control and three epidemiologic), assessed the risk of cardiovascular accidents (CVAs), ischemic heart disease, and/or peripheral arterial disease in patients with IBD compared to non-IBD patients. The risk of cardiovascular disease including ischemic heart disease was 18% increase in patients with IBD (OR ¼ 1.18; 95% CI: 1.08–1.31) as compared to non-IBD patients. Stratifying according to sex, the risk was significantly increased in women only (OR ¼ 1.26; 95% CI: 1.18–1.35). Interestingly, another meta-analysis [26] using slightly other inclusions criteria did not observe a significantly increased risk of IHD among IBD patients, but the magnitude of risk was fairly similar (RR ¼ 1.23; 95% CI: 0.94– 1.62). The difference in the two meta-analyses was mainly that in the previously described cross-sectional study [20], finding an inverse relation was included in the later metaanalysis only. To summarize, most studies suggest a modestly increased relative risk of coronary artery disease in patients with both ulcerative colitis and Crohn's disease, and the risk seems to be higher in women. In general, data on absolute risk are lacking, which are important information when putting the entire puzzle together.
Biochemical changes in inflammatory bowel disease and coronary heart disease Immune cells dominate early atherosclerotic lesions, and their effector molecules accelerate progression of the lesion. A spectrum of several immune-mediated molecules inflammatory cytokines, proteases, coagulation factors, free oxygen radicals, and vasoactive molecules can destabilize and inhibit the formation of a stable fibrous cap, attack cap collagen, and thereby initiate plaque activation, thrombus formation, leading to ischemia [27]. There are several common inflammation-associated biochemical changes observed in IBD and coronary heart disease [28]. For example, levels of C-reactive protein (CRP) are frequently elevated during active disease in patients with IBD, and elevated CRP is independently associated with increased risk of cardiovascular events [29]. Also, abnormalities in platelet number (reactive thrombocytosis), size (reduced mean platelet volume), and density (augmented granular content) are correlated to disease activity in IBD [30], and in addition to their role in hemostasis and thrombosis, platelets also regulate a variety of inflammatory
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responses and are the key factor in atherothrombosis [31]. Calprotectin, an acute phase reactant mainly produced by neutrophils, is increased in a variety of inflammatory disorders including IBD. In IBD, calprotectin concentrations correlate with endoscopic and histological signs of IBD activity [32]. Raised levels of calprotectin are also predictive of cardiovascular events, independent of conventional cardiovascular risk factors [33]. However, the impact of these shared biochemical changes on the association between IBD and coronary heart disease remains unclear.
Risk factors for coronary heart disease in inflammatory bowel disease Traditional risk factors for cardiovascular disease such as diabetes, hyperlipidemia, hypertension, obesity, and smoking are not found to be generally overrepresented in patients with IBD [34]. However, the majority of studies that examined the risk of cardiovascular disease in IBD [17,18,20,22,35,36] do not adequately adjust or have incomplete data for obesity or smoking status. In general, IBD patients have lower body mass index (BMI) compared to the general population [37], and it is thus unlikely that obesity is a significant risk factor for cardiovascular disease in patients with IBD. Considering tobacco smoking, it might act in a double-edged way on the course of IBD (and thereby on the inflammatory burden), meaning that some patients with ulcerative colitis develop a milder disease course, while they are currently smoking, whereas smoking increases disease activity and complications in patients with Crohn's disease [38], although the mechanism and the direct causality behind this phenomenon remain unclear. Despite the greater percentage of smokers among patients Crohn's disease than ulcerative colitis patients, studies on the risk of coronary heart disease among IBD patients do not observe a markedly different risk according to subtype of IBD. Hypercholesterolemia is a known risk factor for cardiovascular morbidity/atherosclerosis, and recommendations for treatment of dyslipidemia are continuously updated [39]. In the organism, cholesterol originates from two principal processes: absorption from the diet and de novo synthesis [40]. However, absorption and synthesis of cholesterol might be impaired during active disease, malnutrition, and surgical treatment, which may lead to low-lipid levels in patients with IBD. In a review from 2008 examining lipid abnormalities in patients with IBD, authors concluded, on the basis on nine studies, that IBD patients exhibit lower levels of low-density lipoprotein cholesterol (LDL-C) and total cholesterol compared to healthy subjects, most pronounced for patients with Crohn's disease. Normally, the low-lipid levels would have a positive impact on the risk of cardiovascular disease. However, studies [41] have observed a paradoxical inversion of the association between cardiovascular risk and lipid levels in conditions with systemic inflammation such as IBD. Only a few studies have analyzed the burden of risk factors for cardiovascular disease among IBD patients. A small crosssectional study [42] (42 cases and 137 controls) using the Framingham risk score (10 years risk score based on age, hypertension, diabetes mellitus, tobacco use, and dyslipidemia)
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evaluated the presence of risk factors among IBD and non-IBD patients with cardiovascular disease. Interestingly, they found the Framingham risk score to be lower in IBD patients compared to non-IBD patients (8.1 vs. 10.0; P ¼ .002) [42]. A case–control study from the US [43] on 131 IBD patients and 524 matched non-IBD patients with coronary artery disease (diagnosed by cardiac catheterization) examined for conventional risk factors and cardiovascular outcomes and observed that IBD patients were younger, had lower prevalence of active tobacco use, and a lower body mass index compared to nonIBD patients. The authors also observed trends of less frequent occurrence of multi-vessel cardiovascular disease and severe left artery disease in IBD patients compared to non-IBD patients. Post-percutaneous coronary intervention (PCI) outcomes were similar among IBD and non-IBD patients. Hence, using conventional risk scores to predict risk of cardiovascular events might not accurately identify patients with IBD who are at risk of cardiovascular disease.
Carotid intima–media thickness and arterial stiffness in inflammatory bowel disease Inflammation with elevated levels of pro-inflammatory cytokines may promote vascular changes leading to increased arterial stiffness and carotid intima thickness, both subclinical markers for atherosclerosis. Thus, one could assume that the chronic inflammation in patients with IBD may act as an untraditional risk factor for cardiovascular disease. Smooth muscle cell hyperplasia, an initial stage of atherosclerosis, is leading to increased carotid intima–media thickness, which is measurable, and commonly used as a marker for early atherosclerosis. However, the evidence of an increased carotid intima–media thickness following chronic inflammation in patients with IBD is still sparse, and the few available results are contradicting as clarified in a systematic review [44]. The review included six studies; three studies reported an increased carotid intima–media thickness, whereas the other three did not. All of the included studies were small, and study populations differed in characteristics such as disease phenotype, disease duration, and smoking behavior. Another subclinical measure of atherosclerosis is arterial stiffness, which is a consequence of vascular fibrosis and elastic fiber degradation of the large arteries. Although increased arterial stiffness is highly correlated to the aging process, it is also a surrogate marker of cardiovascular disease. In a single-center study, traditional risk factors for cardiovascular disease, level of inflammatory markers, and arterial stiffness by brachial–ankle pulse wave velocity were compared in patients with rheumatoid arthritis (n ¼ 43), IBD (n ¼ 42), and healthy controls [45]. Authors observed that brachial–ankle pulse wave velocity did not differ significantly among groups, and that ankle–brachial index was modestly lower in IBD patients than controls. In addition, patients with rheumatoid arthritis were found to have higher levels of CRP compared to IBD patients, and it was concluded that traditional risk factors, and not inflammatory markers, were the major parameters associated to arterial stiffness [45]. Somewhat contradictory to this, another study [46] on 32 fairly
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younger IBD patients (age 19–49 years) without cardiovascular risk factors observed an increased arterial stiffness in IBD patients compared to 32 healthy controls. The authors also observed an increase in carotid–radial pulse wave velocity related to disease duration, which may be seen as a surrogate marker of the inflammatory burden. However, to clarify whether chronic inflammation and arterial stiffness explain the cardiovascular risk observed in patients with IBD, larger studies are warranted.
Medical impact on risk of coronary heart disease As chronic inflammation seems to be an important nontraditional risk factor for the development of cardiovascular disease, it is tempting to believe that risk of cardiovascular disease is influenced by treatment with drugs, lowering the inflammation in patients with IBD. However, only a few studies [21,22] have examined the effect of traditional medications for IBD on risk of IHD. Further, most studies are not able to separate the effects of treatment and confounding by indication (the fact that it is often those with more severe disease that get a specific drug, and they may per se carry a higher risk for cardiovascular disease than those with milder disease). A Danish population-based study [22] comparing risk of ischemic heart disease among users and non-users within the IBD population, observed that patients receiving 5-ASA, which might possess aspirin-like properties [47], had a decreased risk of IHD as compared to patients never receiving 5-ASA. This was observed both among patients with CD and UC, and when restricting to long-term use (3þ redeemed prescriptions). Stratification by use of oral corticosteroids, as a proxy for disease activity, further showed that the protective effect of 5-ASA persisted among patients in need for treatment with oral corticosteroids. In the same study as described above, the authors observed a trend toward lower risk of IHD in patients treated with thiopurines and/or TNF-α antagonists, most pronounced among users of both drugs as compared to non-users of these drugs [22]. This is interesting considering that use of these drugs might also reflect disease severity, which is why use could be expected to associate with an increased risk of IHD. Examining medical impact on arterial stiffness in IBD, a study [48] on 32 IBD patients without cardiovascular risk factors observed an increase in carotid–femoral PWV during follow-up (average 3.4 years 7 0.5 years) in patients using salicylates, whereas patients on steroids, azathioprine, or TNF-alpha blockers had almost unmodified carotid–femoral pulse wave velocity during follow-up. Interestingly, studies have found convincing beneficial effects of TNF-α antagonists treatment on the risk of cardiovascular disease in patients with rheumatoid arthritis [49,50].
Conclusion Based on the current evidence, it seems acceptable to acknowledge that patients with IBD have a modestly increased risk of coronary heart disease. In addition, it seems that especially younger and female IBD patients are at
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Table – Characteristic of Crohn's disease and ulcerative colitis. Characteristics
Crohn's disease
Ulcerative colitis
Location
Inflammation may occur anywhere along the digestive tract Discontinuous lesions, inflammation may occur in patches, cobblestone formation Transmural
Inflammation occurs in the rectum and colon (backwash ileitis may occur) Continuous lesions, ulcers, pseudopolyps
Endoscopic findings Histologic findings
Limited to mucosa and submucosa
Symptoms/Objevtive findings to Symptoms
Diarrhea Fever and fatigue Abdominal pain and cramping Bloody stools Reduced appetite Unintended weight loss Mouth sores Malabsorption Anemia Perianal disease
Diarrhea Fever and fatigue Abdominal pain and cramping Bloody stools Reduced appetite Unintended weight loss Rectal bleeding Pus/mucus secretion Anemia
Complications
Strictures Abscesses Fistulas Fissures
Toxic mega colon Colon perforation
increased risk, whereas subtype of IBD itself does not seems to influence risk. The reason for the increased risk remains uncertain. However, the potential that inflammation acts as non-traditional risk factors in patients with IBD is a reasonable suggestion. To what extent IBD medications modify the risk of coronary heart disease is also partly unresolved, and future studies evaluating this perspective are needed. In addition, the impact of early atherosclerosis in patients with IBD needs further investigation. Currently, there are no guidelines present for the surveillance and treatment of cardiovascular disease in patients with IBD and it is debatable whether this is needed based on the lack of information on absolute risk of this condition in patients with IBD. However, we recommend that the clinicians be aware of the moderate increased risk, in particular the absence of traditional risk factors, when faced with a patient with IBD (Table).
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Inflammatory bowel disease and risk of coronary heart disease Christine Rungoen, Nynne Nyboe Andersen, and Tine Jess Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen, Denmark
abstra ct Emerging data have shown consistent evidence of an association between inflammation and development of atherosclerosis. Systemic autoimmune diseases are characterized by chronic inflammation and immune dysregulation, and diseases such as rheumatoid arthritis and lupus erythematosus are now commonly accepted to associate with development of cardiovascular disease, including coronary artery disease. However, the risk of cardiovascular disease in inflammatory bowel disease (IBD), a chronic inflammatory disease of the gut, is still unclear and the magnitude of a potentially increased risk is continuously debated. The aim of this review is to give an update on the existing literature on the association between inflammatory bowel disease and risk of cardiovascular disease, in particular coronary artery disease, and further to discuss traditional and non-traditional risk factors in patients with inflammatory bowel disease. & 2015 Elsevier Inc. All rights reserved.
Coronary heart disease Coronary heart disease (CHD) and myocardial infarction (MI) are major causes of morbidity and mortality worldwide [1]. In the past, cardiovascular disease prevention has focused on the role of lifestyle risk factors, such as body weight, smoking, cholesterol levels, fat consumption, exercise infrequency, and blood pressure, and the objective has been to reduce the levels of these factors [2]. However, increasing evidence suggests that inflammation plays an essential role in atherogenesis [3], as it acts as a key regulatory process linking multiple risk factors for atherosclerosis [4]. It is, therefore, natural to investigate the occurrence of atherosclerosis among patients with systemic inflammatory diseases. Cardiovascular manifestations of rheumatologic diseases have gradually become recognized, particularly coronary heart disease [5], and it is therefore recommended to monitor patients with rheumatologic diseases carefully to assure early recognition, management, and treatment of cardiovascular disease to improve the long-term outcome in these patients [5]. In patients with inflammatory bowel disease (IBD), evidence The authors have indicated that there are no conflicts of interest. n Corresponding author. Tel.: þ45 207 624 77. E-mail address: [email protected] (C. Rungoe). http://dx.doi.org/10.1016/j.tcm.2015.03.010 1050-1738/& 2015 Elsevier Inc. All rights reserved.
is limited and no management guidelines have been recommended for these patients.
Inflammatory bowel disease Crohn's disease and ulcerative colitis, referred to as inflammatory bowel disease (IBD), are chronic intestinal diseases of multifactorial etiology, ——a result of an interaction between a predisposing genetic background and various environmental factors [6,7]. Ulcerative colitis and Crohn's disease are characterized by a chronic relapsing or continuous disease course with intestinal inflammation, causing gastrointestinal symptoms such as diarrhea, passage of blood, pus, or mucus, abdominal pain, fever, and weight loss. In patients with ulcerative colitis, the inflammation is limited to the mucosal layer of the colon; it almost consistently involves the rectum and extends in a proximal and continuous manner to involve other parts of the colon. Crohn's disease is characterized by transmural inflammation, which can lead to fibrosis and obstructive clinical presentations, and it can occur as skip
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lesions throughout the gastrointestinal tract [8–10]. The incidence of IBD is increasing in North America [11,12], Europe [13], as well as in Asia [14]. Treatment strategies for inflammatory bowel disease primarily focus on reducing the intestinal inflammatory burden, either by surgical treatment or/and by medical treatment. Since the middle of the 20th century, the medical treatment of both Crohn's disease and ulcerative colitis primarily consisted of 5-aminosalicylic acid preparations (5-ASA) and corticosteroids in case of flares. However, in the past 30 years, major advances in medical treatment of IBD have been made, with the introduction of thiopurines and latest tumor necrosis factor alpha (TNFalpha) blockers (late 1990s). Extra-intestinal manifestations in patients with IBD are common, and include, among others, manifestations in the ocular, dermatologic, musculoskeletal, and hepatopancreatobiliary system [15]. The fact that approximately one-third of patients with IBD present with at least one extra-intestinal manifestation has led to the suggestion that IBD is a systemic disorder with predominant manifestations in the bowel. Systemic or local, the inflammatory burden in IBD varies between patients and may relate to disease duration, extent of intestinal involvement, and disease activity. The great heterogeneity in inflammatory burden within the IBD population makes it a challenge to evaluate the overall risk and risk factors for coronary heart disease in patients with IBD. We aimed to review existing literature on the occurrence of cardiovascular disease, with focus on coronary artery disease, among patients with inflammatory bowel disease and to address the controversies that surround it.
Methodology/review criteria Preparing this review, a systematic literature search was performed using PubMed, MEDLINE, and EMBASE databases from inception until January 2015, as well as review of article bibliographies, for all relevant English language articles on the risk of ischemic heart disease in patients with IBD. Search terms used were “ischemic heart disease,” “coronary heart disease,” “myocardial infarction,” “atherosclerosis,” and “thromboembolism/arterial” in combination with key words “inflammatory bowel disease,” “ulcerative colitis,” or “Crohn's disease.”
Inflammatory bowel disease and risk of coronary heart disease The association between venous thromboembolic events and IBD is well established [16], and precautions for hospitalized patients are taken. However, there are no such recommendations for arterial thromboembolic events and the topic is still debatable. In the year 2000, a large registry-based IBD study [17] from Canada was among the first to describe an increased risk of ischemic heart disease (IHD) in a populationbased setting. IBD patients (n ¼ 8060) were found to have a 26% increased risk of ischemic heart disease (IRR ¼ 126; 95% CI: 1.11–1.44) compared to non-IBD patients (n ¼ 80,489). Whereas CD and UC patients had similar risk of IHD, women
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carried a higher risk than men did. In accordance, another population-based study from the US, using data from a discharge database [18], observed that only an increased risk of myocardial infarction in women with IBD aged more than 40 years (HR ¼ 1.6; P ¼ 0.003), after adjustment for potential confounders, including hypertension, diabetes, dyslipidemia, and use of contraceptives. A more substantial risk was described from a smaller single-center study also from the US, which found a 4-fold increased risk of coronary heart events among IBD patients [19] (HR ¼ 4.08; 95% CI: 2.49–6.70) compared to non-IBD patients who were hospitalized for other reasons at the same hospital. Although the authors were able to control for a variety of potential confounders and found IBD patients to have a lower burden of traditional risk factors, their population might not be generalizable, being from a single-center hospital and comprising mostly Hispanic and low-income individuals. A cross-sectional study [20] using a nationwide inpatient sample of IBD patients and hospitalized patients as controls observed an inverse relation between IBD and IHD (OR ¼ 0.60; 95% CI: 0.56–0.65). However, these results may be interpreted with caution, as results might be influenced by selection bias; assessment of a select subset of more severely ill patients in a tertiary center or due to methodological issue; comparison with a selected control population. A study from the UK General Practice Research Database [21] on 15,498 patients with ulcerative colitis and 9829 patients with Crohn's disease, found an increased risk of acute myocardial infarction among IBD patients in analysis without adjustment. However, adjustment for potential confounders including age, sex, previously hypertension, diabetes, hypercholesterolemia, smoking status, body mass index, and aspirin use attenuated the association. However, this might be due to selective assessment of the less severely ill part of the IBD population. A nationwide registry-based Danish study [22] of 4.6 million individuals including 28,833 patients with IBD, observed a modestly increased risk of ischemic heart disease in patients with IBD. The risk of ischemic heart disease (IHD) was 2-fold increased during the first year after IBD diagnosis and approximately 20% increased during 1–13 years after diagnosis when taking age, gender, calendar year, socioeconomic status, use of glucose-lowering medications, cardiovascular drugs, and treatment for hypercholesterolemia into account. Risk estimates were similar in patients with Crohn's disease and ulcerative colitis, whereas women had increased risk compared to that of men. In line with this, a subsequent Danish registry-based study [23] on a similar population, examined risk of myocardial infarction in IBD patients according to proxies for disease activity (dividing time after first IBD diagnosis into periods of flare, persistent activity or remission depended on need of corticosteroids, anti-TNF-alpha treatment, or hospitalization). The authors found that IBD patients had an increased risk of MI during flares (IRR ¼ 1.49; 95% CI: 1.16–1.93), and persistent activity (IRR ¼ 2.05; 95% CI: 158–265), (flares defined as need for medical treatment or hospitalization within 120 days after a flare), but no increased risk during remission (IRR ¼ 1.01; 95% CI: 0.89–1.15) was observed. However, both the risk of ascertainment bias and acute illness (including hypovolemia and anemia), which per se is associated with
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increased short-term risk of cardiovascular events, may contribute to this association. However, in line with this, a Swedish study [24] examined the risk of coronary heart disease among patients hospitalized for immune-mediated diseases including ulcerative colitis and Crohn's disease also observed an increased risk of coronary heart disease among hospitalized patients with UC (SIR ¼ 1.21; 95% CI: 1.17–1.26), and a very modestly increased risk in patients with CD (SIR ¼ 1.06; 95% CI: 1.01–1.12), after adjustment for age, period, socioeconomic factor and hospitalization chronic lower respiratory disease, obesity, alcoholism, hypertension, diabetes, arterial flutter or heart failure and renal disease). A systematic review and meta-analysis [25] on risk of cardiovascular disease in IBD patients, including nine studies (six case–control and three epidemiologic), assessed the risk of cardiovascular accidents (CVAs), ischemic heart disease, and/or peripheral arterial disease in patients with IBD compared to non-IBD patients. The risk of cardiovascular disease including ischemic heart disease was 18% increase in patients with IBD (OR ¼ 1.18; 95% CI: 1.08–1.31) as compared to non-IBD patients. Stratifying according to sex, the risk was significantly increased in women only (OR ¼ 1.26; 95% CI: 1.18–1.35). Interestingly, another meta-analysis [26] using slightly other inclusions criteria did not observe a significantly increased risk of IHD among IBD patients, but the magnitude of risk was fairly similar (RR ¼ 1.23; 95% CI: 0.94– 1.62). The difference in the two meta-analyses was mainly that in the previously described cross-sectional study [20], finding an inverse relation was included in the later metaanalysis only. To summarize, most studies suggest a modestly increased relative risk of coronary artery disease in patients with both ulcerative colitis and Crohn's disease, and the risk seems to be higher in women. In general, data on absolute risk are lacking, which are important information when putting the entire puzzle together.
Biochemical changes in inflammatory bowel disease and coronary heart disease Immune cells dominate early atherosclerotic lesions, and their effector molecules accelerate progression of the lesion. A spectrum of several immune-mediated molecules inflammatory cytokines, proteases, coagulation factors, free oxygen radicals, and vasoactive molecules can destabilize and inhibit the formation of a stable fibrous cap, attack cap collagen, and thereby initiate plaque activation, thrombus formation, leading to ischemia [27]. There are several common inflammation-associated biochemical changes observed in IBD and coronary heart disease [28]. For example, levels of C-reactive protein (CRP) are frequently elevated during active disease in patients with IBD, and elevated CRP is independently associated with increased risk of cardiovascular events [29]. Also, abnormalities in platelet number (reactive thrombocytosis), size (reduced mean platelet volume), and density (augmented granular content) are correlated to disease activity in IBD [30], and in addition to their role in hemostasis and thrombosis, platelets also regulate a variety of inflammatory
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responses and are the key factor in atherothrombosis [31]. Calprotectin, an acute phase reactant mainly produced by neutrophils, is increased in a variety of inflammatory disorders including IBD. In IBD, calprotectin concentrations correlate with endoscopic and histological signs of IBD activity [32]. Raised levels of calprotectin are also predictive of cardiovascular events, independent of conventional cardiovascular risk factors [33]. However, the impact of these shared biochemical changes on the association between IBD and coronary heart disease remains unclear.
Risk factors for coronary heart disease in inflammatory bowel disease Traditional risk factors for cardiovascular disease such as diabetes, hyperlipidemia, hypertension, obesity, and smoking are not found to be generally overrepresented in patients with IBD [34]. However, the majority of studies that examined the risk of cardiovascular disease in IBD [17,18,20,22,35,36] do not adequately adjust or have incomplete data for obesity or smoking status. In general, IBD patients have lower body mass index (BMI) compared to the general population [37], and it is thus unlikely that obesity is a significant risk factor for cardiovascular disease in patients with IBD. Considering tobacco smoking, it might act in a double-edged way on the course of IBD (and thereby on the inflammatory burden), meaning that some patients with ulcerative colitis develop a milder disease course, while they are currently smoking, whereas smoking increases disease activity and complications in patients with Crohn's disease [38], although the mechanism and the direct causality behind this phenomenon remain unclear. Despite the greater percentage of smokers among patients Crohn's disease than ulcerative colitis patients, studies on the risk of coronary heart disease among IBD patients do not observe a markedly different risk according to subtype of IBD. Hypercholesterolemia is a known risk factor for cardiovascular morbidity/atherosclerosis, and recommendations for treatment of dyslipidemia are continuously updated [39]. In the organism, cholesterol originates from two principal processes: absorption from the diet and de novo synthesis [40]. However, absorption and synthesis of cholesterol might be impaired during active disease, malnutrition, and surgical treatment, which may lead to low-lipid levels in patients with IBD. In a review from 2008 examining lipid abnormalities in patients with IBD, authors concluded, on the basis on nine studies, that IBD patients exhibit lower levels of low-density lipoprotein cholesterol (LDL-C) and total cholesterol compared to healthy subjects, most pronounced for patients with Crohn's disease. Normally, the low-lipid levels would have a positive impact on the risk of cardiovascular disease. However, studies [41] have observed a paradoxical inversion of the association between cardiovascular risk and lipid levels in conditions with systemic inflammation such as IBD. Only a few studies have analyzed the burden of risk factors for cardiovascular disease among IBD patients. A small crosssectional study [42] (42 cases and 137 controls) using the Framingham risk score (10 years risk score based on age, hypertension, diabetes mellitus, tobacco use, and dyslipidemia)
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evaluated the presence of risk factors among IBD and non-IBD patients with cardiovascular disease. Interestingly, they found the Framingham risk score to be lower in IBD patients compared to non-IBD patients (8.1 vs. 10.0; P ¼ .002) [42]. A case–control study from the US [43] on 131 IBD patients and 524 matched non-IBD patients with coronary artery disease (diagnosed by cardiac catheterization) examined for conventional risk factors and cardiovascular outcomes and observed that IBD patients were younger, had lower prevalence of active tobacco use, and a lower body mass index compared to nonIBD patients. The authors also observed trends of less frequent occurrence of multi-vessel cardiovascular disease and severe left artery disease in IBD patients compared to non-IBD patients. Post-percutaneous coronary intervention (PCI) outcomes were similar among IBD and non-IBD patients. Hence, using conventional risk scores to predict risk of cardiovascular events might not accurately identify patients with IBD who are at risk of cardiovascular disease.
Carotid intima–media thickness and arterial stiffness in inflammatory bowel disease Inflammation with elevated levels of pro-inflammatory cytokines may promote vascular changes leading to increased arterial stiffness and carotid intima thickness, both subclinical markers for atherosclerosis. Thus, one could assume that the chronic inflammation in patients with IBD may act as an untraditional risk factor for cardiovascular disease. Smooth muscle cell hyperplasia, an initial stage of atherosclerosis, is leading to increased carotid intima–media thickness, which is measurable, and commonly used as a marker for early atherosclerosis. However, the evidence of an increased carotid intima–media thickness following chronic inflammation in patients with IBD is still sparse, and the few available results are contradicting as clarified in a systematic review [44]. The review included six studies; three studies reported an increased carotid intima–media thickness, whereas the other three did not. All of the included studies were small, and study populations differed in characteristics such as disease phenotype, disease duration, and smoking behavior. Another subclinical measure of atherosclerosis is arterial stiffness, which is a consequence of vascular fibrosis and elastic fiber degradation of the large arteries. Although increased arterial stiffness is highly correlated to the aging process, it is also a surrogate marker of cardiovascular disease. In a single-center study, traditional risk factors for cardiovascular disease, level of inflammatory markers, and arterial stiffness by brachial–ankle pulse wave velocity were compared in patients with rheumatoid arthritis (n ¼ 43), IBD (n ¼ 42), and healthy controls [45]. Authors observed that brachial–ankle pulse wave velocity did not differ significantly among groups, and that ankle–brachial index was modestly lower in IBD patients than controls. In addition, patients with rheumatoid arthritis were found to have higher levels of CRP compared to IBD patients, and it was concluded that traditional risk factors, and not inflammatory markers, were the major parameters associated to arterial stiffness [45]. Somewhat contradictory to this, another study [46] on 32 fairly
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younger IBD patients (age 19–49 years) without cardiovascular risk factors observed an increased arterial stiffness in IBD patients compared to 32 healthy controls. The authors also observed an increase in carotid–radial pulse wave velocity related to disease duration, which may be seen as a surrogate marker of the inflammatory burden. However, to clarify whether chronic inflammation and arterial stiffness explain the cardiovascular risk observed in patients with IBD, larger studies are warranted.
Medical impact on risk of coronary heart disease As chronic inflammation seems to be an important nontraditional risk factor for the development of cardiovascular disease, it is tempting to believe that risk of cardiovascular disease is influenced by treatment with drugs, lowering the inflammation in patients with IBD. However, only a few studies [21,22] have examined the effect of traditional medications for IBD on risk of IHD. Further, most studies are not able to separate the effects of treatment and confounding by indication (the fact that it is often those with more severe disease that get a specific drug, and they may per se carry a higher risk for cardiovascular disease than those with milder disease). A Danish population-based study [22] comparing risk of ischemic heart disease among users and non-users within the IBD population, observed that patients receiving 5-ASA, which might possess aspirin-like properties [47], had a decreased risk of IHD as compared to patients never receiving 5-ASA. This was observed both among patients with CD and UC, and when restricting to long-term use (3þ redeemed prescriptions). Stratification by use of oral corticosteroids, as a proxy for disease activity, further showed that the protective effect of 5-ASA persisted among patients in need for treatment with oral corticosteroids. In the same study as described above, the authors observed a trend toward lower risk of IHD in patients treated with thiopurines and/or TNF-α antagonists, most pronounced among users of both drugs as compared to non-users of these drugs [22]. This is interesting considering that use of these drugs might also reflect disease severity, which is why use could be expected to associate with an increased risk of IHD. Examining medical impact on arterial stiffness in IBD, a study [48] on 32 IBD patients without cardiovascular risk factors observed an increase in carotid–femoral PWV during follow-up (average 3.4 years 7 0.5 years) in patients using salicylates, whereas patients on steroids, azathioprine, or TNF-alpha blockers had almost unmodified carotid–femoral pulse wave velocity during follow-up. Interestingly, studies have found convincing beneficial effects of TNF-α antagonists treatment on the risk of cardiovascular disease in patients with rheumatoid arthritis [49,50].
Conclusion Based on the current evidence, it seems acceptable to acknowledge that patients with IBD have a modestly increased risk of coronary heart disease. In addition, it seems that especially younger and female IBD patients are at
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Table – Characteristic of Crohn's disease and ulcerative colitis. Characteristics
Crohn's disease
Ulcerative colitis
Location
Inflammation may occur anywhere along the digestive tract Discontinuous lesions, inflammation may occur in patches, cobblestone formation Transmural
Inflammation occurs in the rectum and colon (backwash ileitis may occur) Continuous lesions, ulcers, pseudopolyps
Endoscopic findings Histologic findings
Limited to mucosa and submucosa
Symptoms/Objevtive findings to Symptoms
Diarrhea Fever and fatigue Abdominal pain and cramping Bloody stools Reduced appetite Unintended weight loss Mouth sores Malabsorption Anemia Perianal disease
Diarrhea Fever and fatigue Abdominal pain and cramping Bloody stools Reduced appetite Unintended weight loss Rectal bleeding Pus/mucus secretion Anemia
Complications
Strictures Abscesses Fistulas Fissures
Toxic mega colon Colon perforation
increased risk, whereas subtype of IBD itself does not seems to influence risk. The reason for the increased risk remains uncertain. However, the potential that inflammation acts as non-traditional risk factors in patients with IBD is a reasonable suggestion. To what extent IBD medications modify the risk of coronary heart disease is also partly unresolved, and future studies evaluating this perspective are needed. In addition, the impact of early atherosclerosis in patients with IBD needs further investigation. Currently, there are no guidelines present for the surveillance and treatment of cardiovascular disease in patients with IBD and it is debatable whether this is needed based on the lack of information on absolute risk of this condition in patients with IBD. However, we recommend that the clinicians be aware of the moderate increased risk, in particular the absence of traditional risk factors, when faced with a patient with IBD (Table).
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